The sucrose molecule contains three primary hydroxyl groups and five secondary hydroxyl groups. Therefore, when it is desired to prepare derivatives of sucrose involving reaction of the hydroxyl groups, it can be a major synthesis problem to direct the reaction only to the desired hydroxyl groups. For instance, the artificial sweetener 4,1',6'-trichloro-4,1',6'-trideoxygalactosucrose ("sucralose") is derived from sucrose by replacing the hydroxyls in the 4, 1', and 6' positions with chlorine. (In the process of making the sweetener, the stereo configuration at the 4 position is reversed--hence the compound is a galactosucrose.) This compound and methods for synthesizing it are disclosed in U. S. Pat. Nos. 4,343,934, 4,362,869, 4,380,476, and 4,435,440. The direction of the chlorine atoms to only the desired positions is a major synthesis problem, especially since the hydroxyls that are replaced are of differing reactivity (two are primary and one is secondary; the synthesis is further complicated by the fact that the primary hydroxyl in the 6 position is unsubstituted in the final product). The preparation of this sweetener is only one illustration of the synthesis of sucrose derivatives wherein it is desired either to derivatize certain specific hydroxyl groups, and only such hydroxyl groups, or to derivatize only a specified number of the hydroxyls, perhaps in this latter case without particular regard to which particular hydroxyl(s) are derivatized. The preparation of sucrose-based mono-ester surfactants is a commercial example of mono substitution on the sucrose molecule.
This invention provides an improved and more efficient means for synthesizing sucrose compounds such as 6-substituted sucrose derivatives wherein the process of the invention is highly regioselective both with regard to directing the reaction strictly to the 6 position and to the preparation of mono-substituted derivatives only. The term "regioselective" refers to a reaction that highly favors a single major product. (Ref., Hassner, "Regiospecificity. A Useful Terminology in Addition and Elimination Reactions", J. Org. Chem., 33, No. 7, 2684-6, July 1968.)
The distannoxane-based preparation of sucrose-6-esters was first described in Navia, PROCESS FOR SYNTHESIZING SUCROSE DERIVATIVES BY REGIOSELECTIVE REACTION, U.S. patent application Ser. No. 220,641, filed on July 18, 1988 (now U.S. Pat. No. 4,950,746), and assigned to the same assignee as this application. Navia disclosed that a suitable di(hydrocarbyl)tin-based species, such as dibutyltin oxide, dioctyltin oxide, dibutyltin dimethoxide, or the like, can be combined with a hydroxyl group-containing compound such as a monohydric alcohol or a simple phenol in such a way as to produce a reactive distannoxane intermediate [i.e., a 1,3-di(hydrocarbyloxy)-1,1,3,3-tetra(hydrocarbyl)distannoxane], which can then be reacted with sucrose to afford a 1,3-di-(6-O-sucrose)-1,1,3,3-tetra(hydrocarbyl)distannoxane. Navia also described the ready preparation of sucrose-6-esters by the treatment of these organotin-sucrose adducts with a suitable acylating agent in an appropriate solvent or solvent mixture. Navia further described the simple esters acetate and benzoate, prepared from their anhydrides, as preferred protecting groups for sucralose manufacture because of cost, toxicological considerations, and ease of subsequent removal. The process disclosed by Navia for the distannoxane-mediated preparation of sucrose 6-esters ("S-6-E") thus consists of three distinct steps, as follows (using dibutyltin oxide and n-butanol as exemplary reactants):
(1) Reaction of dibutyltin oxide ("DBTO") with a large stoichiometric excess of n-butanol, with azeotropic removal of water, to produce 1,3-dibutoxy-1,1,3,3-tetrabutyldistannoxane ("DBDS"), which has been shown to exist as a monohydrate;
(2) Reaction of DBDS with sucrose in N,N-dimethylformamide ("DMF") with removal of water and n-butanol to form 1,3-di-(6-O-sucrose)-1,1,3,3-tetrabutyldistannoxane, more commonly referred to as dibutylstannoxylsucrose ("DBSS"). Because the acylation reaction of the next step should be done in a hydroxyl-free environment for optimum yield of the sucrose ester product, all the n-butanol and water must be removed during this step and replaced with DMF; and
(3) Reaction of DBSS with a slight stoichiometric excess of an acylating agent such as acetic anhydride to form a sucrose-6-acylate such as sucrose-6-acetate ("S-6-A").
By following this reaction sequence, S-6-A is typically produced in good yields, with only minimal contamination by residual sucrose, sucrose diacetates, and other sucrose monoacetates.
As will be appreciated by those skilled in the art of industrial chemistry, the above-described three-step sequence suffers several drawbacks with regard to economical commercial implementation. These drawbacks become especially serious if commercial implementation using batch-mode processing is desired. The first drawback is the solvent exchange of DMF for n-butanol during DBSS formation. Because of the temperature sensitivity of DBSS in this solvent matrix (decomposition appears to begin at about 90.degree. C.), this solvent exchange must be accomplished as part of a vacuum distillation requiring ever increasing vacuum as the n-butanol content of the mixture declines. Failure to remove sufficient n-butanol results in poor performance in the acetylation reaction of Step (3). Additionally, recycle of the distilled n-butanol is made complex because of its contamination by DMF and water. (Recycling of the n-butanol is required for economic reasons.)
A second drawback of the three-step process is the moisture sensitivity of DBDS (and related condensation products of tin oxides with alcohols or phenols). Even though DBDS apparently exists as a monohydrate, contact with atmospheric moisture results in its rapid reversion to DBTO and n-butanol. DBDS must therefore be handled under conditions designed to rigorously exclude atmospheric moisture. In a manufacturing operation, conditions which resulted in the deposition of DBTO onto the surfaces of the processing equipment would necessitate an expensive clean-up operation because DBTO is a polymeric solid that is quite insoluble in most solvents.
A third drawback involves the recycle of the organotin end-product, distannoxane diacetate ("DSDA"). DSDA is reconverted to DBDS by extraction followed by treatment with either potassium or sodium butoxide. The by-products of these conversions, either potassium or sodium acetate, are difficult to filter. This difficult filtration causes the loss of DBDS, and would be expected to have an adverse impact on S-6-A production cost. Also, as pointed out above, the DBDS must be protected from moisture.
The process of this invention avoids these three problems, and in addition provides a simpler, more economically attractive and less trouble-prone process for the manufacture of sucrose-6-esters. This process is especially suitable for use in the batch-processing mode. We have discovered that sucrose may be directly reacted with di(hydrocarbyl)tin oxides, such as DBTO, in a polar aprotic solvent, such as DMF, in the presence of a cosolvent capable of both promoting the dissolution of DBTO and effecting the codistillative removal of all water generated in the reaction of the tin oxide with sucrose, to produce thereby an organotin-sucrose adduct. This adduct has been shown by NMR to be a distannoxane of a structure identical to that produced by the alcohol-mediated method of Navia (e.g., DBSS). As was the case with the Navia process, the DBSS can be readily acylated in situ to afford good yields of S-6-E.
The process of this invention is an improvement over the alcohol-mediated process of Navia for the following reasons:
(a) one reactant (i.e., an alcohol such as butanol) has been eliminated;
(b) a moisture-sensitive intermediate (e.g., DBDS) has been eliminated;
(c) a complex vacuum distillation-solvent exchange has been eliminated, along with the need to recover n-butanol (or a similar hydroxylic reactant) from mixtures containing DMF and water;
(d) a simplified organotin recycle process, involving an easily filterable di(hydrocarbyl)tin oxide (such as DBTO) rather than a difficultly filterable acetate salt and a moisture-sensitive organotin derivative, is now possible [this recycle process is described in copending United States Patent Application Serial No. (NOR 9), PROCESS FOR RECOVERY OF ORGANOTIN ESTERS FROM REACTION MIXTURES CONTAINING THE SAME AND RE-USE OF THE RECOVERED ORGANOTIN COMPOUNDS, filed on the same day as this application by N. M. Vernon and R. E. Walkup (Vernon et al.), and assigned to the same assignee as this application]; and
(e) sucrose-6-esters, such as S-6-A or sucrose-6-benzoate ("S-6-B"), are obtained in a better yield and in a higher state of purity (apparently the result of eliminating one transition state from the process pathway).